Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells.
Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells.
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DOI：
10.1177/0963689720947102
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发表时间：
2020-01
影响因子：
3.3
通讯作者：
Dufour JM
中科院分区：
文献类型：
--
作者：
Kaur G;Wright K;Mital P;Hibler T;Miranda JM;Thompson LA;Halley K;Dufour JM
急性细胞介导的免疫反应是异种移植的重要障碍。免疫特异型支持细胞(SC)通过保护异种胰岛、肝细胞和神经元等共移植细胞免受免疫排斥反应而延长其存活时间。此外，SC在不使用任何免疫抑制药物的情况下作为异体和异种移植存活，提示阐明SC的存活机制可用于提高异种移植的存活率(S)。在这项研究中，比较了非免疫特权对照的新生猪SC(NPSC)和新生猪胰岛(NPI)的存活和产生的免疫反应。NPSC在整个研究过程中存活下来，而NPI在9天内被拒绝。对移植物的分析表明，巨噬细胞和T细胞是NPSC和NPI移植物的主要免疫细胞。移植物内T细胞的进一步鉴定表明，在早期，NPSC移植物比NPI移植物含有更多的分化簇4(CD4)和分化簇8(CD8)调节性T细胞(Tregs)。此外，与NPI移植物相比，NPSC移植物中白介素10和转化生长因子β的含量增加，肿瘤坏死因子α水平和细胞凋亡水平降低，表明NPSC移植物中存在调节性免疫细胞。神经干细胞表达多种免疫调节因子，如转化生长因子β、凝血酶敏感蛋白-1、吲哚胺-吡咯-2，3-双加氧酶和半乳糖凝集素-1，可促进这些免疫调节细胞向神经干细胞移植物的募集。相比之下，NPI移植物的Treg较少，而凋亡和炎症(增加肿瘤坏死因子α，降低IL-10和转化生长因子β)增加，提示细胞毒性免疫细胞参与了早期排斥反应。综上所述，我们的数据表明，NPSC移植物中具有包括CD4+和CD8+Tregs在内的调节性免疫细胞的调节性移植环境可能归因于NPSC异种移植物的长期存活。
The acute cell-mediated immune response presents a significant barrier to xenotransplantation. Immune-privileged Sertoli cells (SC) can prolong the survival of co-transplanted cells including xenogeneic islets, hepatocytes, and neurons by protecting them from immune rejection. Additionally, SC survive as allo- and xenografts without the use of any immunosuppressive drugs suggesting elucidating the survival mechanism(s) of SC could be used to improve survival of xenografts. In this study, the survival and immune response generated toward neonatal pig SC (NPSC) or neonatal pig islets (NPI), nonimmune-privileged controls, was compared after xenotransplantation into naïve Lewis rats without immune suppression. The NPSC survived throughout the study, while NPI were rejected within 9 days. Analysis of the grafts revealed that macrophages and T cells were the main immune cells infiltrating the NPSC and NPI grafts. Further characterization of the T cells within the grafts indicated that the NPSC grafts contained significantly more cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) regulatory T cells (Tregs) at early time points than the NPI grafts. Additionally, the presence of increased amounts of interleukin 10 (IL-10) and transforming growth factor (TGF) β and decreased levels of tumor necrosis factor (TNF) α and apoptosis in the NPSC grafts compared to NPI grafts suggests the presence of regulatory immune cells in the NPSC grafts. The NPSC expressed several immunoregulatory factors such as TGFβ, thrombospondin-1 (THBS1), indoleamine-pyrrole 2,3-dioxygenase, and galectin-1, which could promote the recruitment of these regulatory immune cells to the NPSC grafts. In contrast, NPI grafts had fewer Tregs and increased apoptosis and inflammation (increased TNFα, decreased IL-10 and TGFβ) suggestive of cytotoxic immune cells that contribute to their early rejection. Collectively, our data suggest that a regulatory graft environment with regulatory immune cells including CD4 and CD8 Tregs in NPSC grafts could be attributed to the prolonged survival of the NPSC xenografts.
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影响因子：
3.4
作者：
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通讯作者：
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